Development of personalised medicine approaches for the clinical application of IAP antagonists in metastatic and high risk early stage colorectal cancer- ( SFI Investiagator Award)

Colorectal cancer (CRC) has the second highest mortality rate of any cancer in Europe. Globally, there are 1.2 million cases diagnosed each year. For current therapies, the weekly cost per patient can reach €5,000, but benefits to patients are limited. 5-year survival rates have increased only moderately in the past 25 years, indicating a need for novel therapies that target cancer resistance. However, devising new therapies but not knowing which patients will ultimately benefit from these is unsustainably costly. Based on novel diagnostic tools and a substantial body of biomedical, pre-clinical and clinical data generated by the applicant group, this proposal explores the hypothesis that subgroup(s) of colorectal tumours become addicted to inhibitor-of-apoptosis (IAP) proteins, thereby suppressing both apoptosis and immune signalling, and that such subgroup(s) can be effectively treated by novel IAP-targeted therapeutic drugs. We will identify sub-groups of patients not benefiting from current chemotherapy, examine which subgroup(s) of tumours are re-sensitized by IAP antagonist therapy, and will deliver a new generation of systems-based patient stratification tools for future integration into ‘smart’ clinical trials. Our proposal will deliver new solutions for the personalised therapy of CRC, and addresses these in a systematic, step-wise manner.Project ends 2017 Funded by SFI PI- Prof. Jochen Prehn

************************************************************************************

A systems-based patient stratification tool of Bcl-2 family protein interactions to evaluate acute treatment responses in rectal cancer patients Cancers of the rectum (the lower part of the large intestine where the body stores stool) are a common cause of cancer-related death in Ireland and cause a significant burden to the quality of life of affected patients. Surgery is the mainstay for the treatment of rectal cancer, but surgeons often prefer to ‘downstage’ or ‘shrink’ the tumour prior to surgery in order to achieve a better surgical outcome and to reduce surgical complications or the necessity of a stoma. This ‘downstaging’ of the tumour is achieved through aggressive radio- and chemotherapy over a period of 2-3 months, however many patients will not respond to this treatment because their cancer cells are resistant to such therapy. Hence for a majority of patients the radiochemotherapy may not only be unnecessary, but may even delay surgery and increase the risk of further tumour progression. In a previous, successful study in colon and rectal cancer patients 1, we developed a new test that is capable of telling the surgical and medical teams whether a patient will respond or not to radiochemotherapy by analysing a set of proteins from a small biopsy of the tumour that is routinely taken during medical examination. Rather than looking at individual proteins or genes, this diagnostic test takes into account the complex regulation of tumour cell death in response to radiochemotherapy. Here we will validate this new diagnostic tool in a larger cohort of rectal cancer patients, and will further improve it by investigating whether the inclusion of important genetic and other patient data increases its predictive power. Finally, we will investigate whether this new diagnostic tool can also be used to identify those patients who may benefit from novel therapeutics that target cell death defects and that are currently in the clinical testing phase. Funded by the HRB; Ends: 30-9-17 PI- Prof. Jochen Prehn Co-applicant(s) First Name Last Name Institution Country 1. Annette Byrne RCSI 2. Bryan Hennessy RCSI

************************************************************************************

BCL-2 family proteins and cellular bioenergetics in the control of cell survival: Towards novel predictive and prognostic markers for disease progression and therapy responses in colorectal cancer patients

Colorectal cancer (CRC) is frequently diagnosed in its later stages where there is local, lymphatic or metastatic spreading, indicating a need for adjuvant or palliative chemotherapy. However, response rates to 5-FU-based chemotherapy remain low.
BCL-2 family proteins and cellular bioenergetics are master regulators of cancer cell survival, and key factors in the development of chemotherapy resistance. Based on experimental and clinical proof-of-concept work, the current programme seeks to identify,
test, and validate novel predictive and prognostic tools centred on an integrated, systems analysis of apoptosis signalling, cellular bioenergetics, and their dependence on genetic/epigenetic signatures in CRC. We will deliver novel signatures and computational
models of tumour responsiveness to genotoxic treatment, and will translate existing and novel computational models of BCL-2 protein interactions and cellular bioenergetics into the clinical setting by evaluating therapy responses in stage 2 and 3 CRC
patients. As a final objective we will identify novel molecular determinants of survival- and death- promoting activities of the energy sensor, AMP-activated- protein-kinase to identify novel biomarkers that may operate cell-autonomously or in paracrine. In
conclusion, the programme will deliver a new generation of diagnostics and systems-based stratification tools designed to facilitate the clinical management of CRC patients.

Funded By SFI ( Investiagator programme award)

PI- Prof. Jochen Prehn

************************************************************************************

Pharmacological inhibition of the paracrine, cell proliferative function of caspase-3 for the treatment of colorectal cancer

Our research group has recently demonstrated that when cells undergo caspase-dependent apoptosis, they send out biochemical signals into their local environment that stimulate the proliferation and differentiation of neighbouring cells. In this project we validate these findings by analysing caspase 3 expression in a large cohort of colorectal cancer patients, and identify whether gene expression and promoter methylation may function as an additional prognostic marker. In a parallel study, we will perform key translational preclinical studies to test the concept that caspase-3 inhibition with the FDA-approved caspase-activation inhibitor Minocycline, or with highly selective caspase-3 inhibitors reduce clonogenic survival in colorectal cancer patient spheroid explant cultures after exposure to 5-Fluorouracil/Oxaliplatin in addition to a pre-clinical xenograft mouse model of colon cancer. This research will deliver novel prognostic markers for therapy success in colorectal cancer.

PI: Jochen Prehn 

Apoptosis Systems Biology Applied to Cancer and AIDS

The APO-SYS consortium aims at obtaining major progress in comprehension of apoptosis (and more generally cell death) in human diseases, by combining a series of systems biology approaches, in silico, in vitro (in organello and in cellula), in vivo and by integrating experimental results with large data sets acquired on tissue samples from patients suffering from diseases that are caused by deregulated apoptosis, in particular cancer and AIDS. The consortium addresses the striking complexity of human cell death pathways using an integrated method involving high-throughput screening, and ”omics” approaches applied to biological systems and computational modeling leading to accurate and disease relevant in silico models of apoptotic signaling triggered along the two principal pathways, the extrinsic pathways (stimulated by ligation of death receptors) and the intrinsic pathways (stimulated by intracellular stress causing mitochondrial membrane permeabilization). Furthermore, the consortium will comparatively asses the system biology of apoptotic and non-apoptotic cell death (necrosis, autophagy and mitotic catastrophe) in order to understand the extent of overlap in the mechanism leading to different phenotypic manifestation of cell death as well as the molecular ”switches” that decide whether cells remain alive or die through one or the other cell death pathway.

This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no HEALTH-F4-2007-200767 for APO-SYS. 

 

 

 

PI:  Jochen Prehn 

 

************************************************************************************

 

Using Systems Medicine to Deliver Personalised Medicine for Colorectal Cancer · FP7 Funded Research Project

New tumour profiling methods developed by EU-funded researchers aim to help doctors adjust treatments for colorectal cancer to the specific needs of an individual patient. The methods are currently at the trial stage and could be in use in clinics within three years.
“Worldwide, colorectal cancer is responsible for around 694 000 deaths each year, according to the World Health Organization. Decision making on treatment in the clinic currently depends largely on factors such as how much the tumour has grown and the age of a patient. As each patient is unique, the success of such treatments is largely unpredictable. To replace the ‘one size fits all’ approach, the APO-DECIDE project, led by Professor Jochen Prehn at the Royal College of Surgeons in Ireland, is developing new clinical decision-making tools to help doctors categorise patients on the basis of their individual biological and genetic characteristics.

”There are numerous genes and pathways altered in human cancers, and no single patient is like another,” says Prof. Prehn. “We now need to employ computational approaches to understand the complexity of genes and protein altered in individual cancer patients.” Such computational approaches (also termed systems biology approaches) use mathematics to explore how proteins interact with each other, and how these interactions produce a biological, clinically relevant effect. Apoptosis Modelling for Treatment Decisions in Colorectal Cancer is a short, focused, 2-year research programme and a partnership with 3 academic institutions (Queen’s University Belfast; Descartes University Paris; University Clinics Frankfurt) and 3 SMEs including two Irish SMEs (Oncomark & Pintail) aimed at exploring and validating the clinical utility of a computational model of effector caspase activation (PCCP) in the context of colorectal cancer, employing automated digital pathology technologies, RPPA analysis, as well as PK/PD modelling.

The APO-DECIDE consortium will tackle the problem of chemotherapy resistance in colorectal cancer. By analyzing protein levels and DNA mutations in individual tumours, and by incorporating these biological data into a complex modeling environment that recapitulates how these entities interact, APO-DECIDE will develop novel diagnostic tools that predict which patients will likely benefit from chemotherapy. It is a hope that these clinical decision-making tools will enable doctors to develop personalized therapies for patients to ensure the best outcomes while potentially avoiding unnecessary chemotherapy and side effects. These new prediction tools may also be used in clinical trials to develop new drugs to treat bowel cancer, enabling ‘smart’ clinical trials design in the future. Commercialization of the project results will be facilitated by OncoMark Ltd. and Optimata Ltd.

Please see the homepage of APO-DECIDE for more details.

Project press release at Horizon 2020: http://ec.europa.eu/programmes/horizon2020/en/news/threshold-personalised-cancer-treatment

This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 306021.

 

 

 

PI: Jochen Prehn 

************************************************************************************

Predictive Genomic Biomarkers Methods for Combination Bevacizumab (Avastin) Therapy in Metastatic Colorectal Cancer

In ANGIOPREDICT, academic cancer biologists and industry-based biotechnology researchers will work together with clinicians to identify biomarkers to predict whether individual metastatic colorectal cancer patients will respond positively to Avastin® combination therapy. Diagnostic tests using these biomarkers will also be developed to provide clinicians with the means to predict patient treatment responses in the future.

Identifying patients who will not respond to Avastin® combination therapy will spare these patients from potential side effects of the treatment. It will also help to prevent relapse, as these patients may ultimately be directed towards alternative, potentially more effective therapies. Health care providers will be able to provide more focused and cost-effective care, because ineffective investment in Avastin® combination therapy will be avoided.

The underlying genomic mechanisms that determine whether or not a patient will respond to Avastin® combination therapy are currently unknown. ANGIOPREDICT aims to unravel these pathways.

The overall approach is as follows:

• ANGIOPREDICT partners will provide previously collected tissue samples from patients receiving Avastin® combination therapy or chemotherapy for genomic analysis. From this analysis, potential predictive biomarkers will be identified.
• The predictive ability of the identified potential biomarkers will then be validated using tissue samples from the AC-ANGIOPREDICT clinical trial, where patients will receive Avastin® combination therapy.
• Validated, predictive biomarkers will then be used to develop diagnostic tests that can be used by clinicians to identify which patients will benefit from Avastin® combination therapy.

This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 278981.

Co-ordinator : Prof Annette Byrne 

Click here for the list of Partners

PI: Jochen Prehn 

************************************************************************************

 

Qualitative and quantitative analysis of factors contributing to apoptosis resistance in colorectal cancer:
Evaluation of new prognostic and therapeutic avenues

The APOCOLON project is a translational project that initially investigated the role of defective apoptosis signalling in CRC and tumor resistance, and builds on the expertise of the applicants in understanding apoptosis resistance at a qualitative and quantitative level. The project established the clinical APO-COLON biocollection at RCSI/Beaumont Hospital, and established the collaborative clinical network described in the current proposdal. It translated recent investigations of the applicants on the role of death receptors, caspases and Bcl-2/BH3 only proteins in tumour sensitivity, with the aim of identifying new prognostic markers for CRC and predicting sensitivity to new clinical treatment paradigms (TRAIL agonists, Bcl-2 antagonists). The project also included the first translation of computational models of caspase and apoptosis activation developed by the applicants to predict tumor responsiveness in patients presenting with CRC.

The project generated key clinical proof-of-concept data, including key publications in Cancer Research and leading gastroenterology journals. It was funded by HRB.

PI: Jochen Prehn 

***********************************************************************************

Pharmacological inhibition of the paracrine, cell proliferative function of caspase-3 for the treatment of colorectal cancer

Our research group has recently demonstrated that when cells undergo caspase-dependent apoptosis, they send out biochemical signals into their local environment that stimulate the proliferation and differentiation of neighbouring cells. In this project we validate these findings by analysing caspase 3 expression in a large cohort of colorectal cancer patients, and identify whether gene expression and promoter methylation may function as an additional prognostic marker. In a parallel study, we will perform key translational preclinical studies to test the concept that caspase-3 inhibition with the FDA-approved caspase-activation inhibitor Minocycline, or with highly selective caspase-3 inhibitors reduce clonogenic survival in colorectal cancer patient spheroid explant cultures after exposure to 5-Fluorouracil/Oxaliplatin in addition to a pre-clinical xenograft mouse model of colon cancer. This research will deliver novel prognostic markers for therapy success in colorectal cancer.

PI: Jochen Prehn